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Around 20% of the Dutch population is living with chronic musculoskeletal pain (CMP), which is a complex and multifactorial problem. This complexity makes it hard to define a classification system, which results in non-satisfactory referring from the general practitioner (GP). CMP is often explained using the biopsychosocial model in which biological, psychological and social factors cause and maintain the pain. The presented study investigated the factors related to the GPs' referral for patients with CMP to further treatment.Using convenience sampling, semi-structured interviews and a focus group were conducted among 14 GPs. The interviews were iteratively analyzed using inductive conventional content analysis.Analysis of the interviews demonstrated that there were 28 referral factors that were mentioned by more than 50% of the interviewed GPs. The results showed that the GPs were mostly focussing on the physical (e.g. pain location) and psychological (e.g. acceptation of pain) factors, indicating that they lack focus on the social factors. Furthermore, unfamiliarity of GPs with treatment options was a noteworthy finding.The referral of patients with CMP by GPs is complex and based on multiple factors. To improve referral, it is recommended to include social factors in the decision-making process and to increase the familiarity of the GPs with available treatments.
Learn More >5-hydroxytryptamine receptor 5A (5-HT) belongs to the 5-HT receptor family and signals through the G protein. It is involved in nervous system regulation and an attractive target for the treatment of psychosis, depression, schizophrenia, and neuropathic pain. 5-HT is the only G-coupled 5-HT receptor subtype lacking a high-resolution structure, which hampers the mechanistic understanding of ligand binding and G coupling for 5-HT. Here we report a cryo-electron microscopy structure of the 5-HT-G complex bound to 5-Carboxamidotryptamine (5-CT). Combined with functional analysis, this structure reveals the 5-CT recognition mechanism and identifies the receptor residue at 6.55 as a determinant of the 5-CT selectivity for G-coupled 5-HT receptors. In addition, 5-HT shows an overall conserved G protein coupling mode compared with other G-coupled 5-HT receptors. These findings provide comprehensive insights into the ligand binding and G protein coupling of G-coupled 5-HT receptors and offer a template for the design of 5-HT-selective drugs.
Learn More >The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential and involved in the development of the peripheral and central nervous system. ALK receptor ligands, ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mice and human peptidergic nociceptors, yet weakly expressed in non peptidergic, large diameter myelinated neurons or in the brain. Using a co-culture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar Complete Freund's adjuvant (CFA) or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds Crizotinib or Lorlatinib, reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2-ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for Non-Small Cell Lung Cancer and neuroblastomas, could be repurposed to treat persistent pain conditions.
Learn More >Trigeminal neuralgia (TN) is a neuropathic pain that occurs in branches of the trigeminal nerve. MicroRNAs (miRNAs) have been considered key mediators of neuropathic pain. This study was aimed to elucidate the pathophysiological function and mechanisms of miR-223-3p in mouse models of TN.
Learn More >Lumbar epidural is the gold standard for labour analgesia. Low concentrations of local anaesthetic are recommended. This network meta-analysis investigated whether further reducing the concentration of local anaesthetic can improve maternal and neonatal outcomes without compromising analgesia. We conducted a systematic search of relevant databases for randomised controlled trials comparing high (>0.1%), low (>0.08% to ≤0.1%) or ultra-low (≤0.08%) concentration local anaesthetic (bupivacaine or equivalent) for labour epidural. Outcomes included mode of delivery, duration of labour and maternal/neonatal outcomes. Bayesian network meta-analysis with random-effects modelling was used to calculate odds ratios or weighted mean differences and 95% credible intervals. A total of 32 studies met inclusion criteria (3665 women). The total dose of local anaesthetic received increased as the concentration increased; ultra-low compared with low (weighted mean difference -14.96 mg, 95% credible interval [-28.38 to -1.00]) and low compared with high groups (weighted mean difference -14.99 [-28.79 to -2.04]), though there was no difference in the number of rescue top-ups administered between the groups. Compared with high concentration, ultra-low concentration local anaesthetic was associated with increased likelihood of spontaneous vaginal delivery (OR 1.46 [1.18 to 1.86]), reduced motor block (Bromage score >0; OR 0.32 [0.18 to 0.54]) and reduced duration of second stage of labour (weighted mean difference -13.02 min [-21.54 to -4.77]). Compared with low, ultra-low concentration local anaesthetic had similar estimates for duration of second stage of labour (weighted mean difference -1.92 min [-14.35 to 10.20]); spontaneous vaginal delivery (OR 1.07 [0.75 to 1.56]; assisted vaginal delivery (OR 1.35 [0.75 to 2.26]); caesarean section (OR 0.76 [0.49 to 1.22]); pain (scale 1-100, weighted mean difference -5.44 [-16.75 to 5.93]); and maternal satisfaction. Although a lower risk of an Apgar score < 7 at 1 min (OR 0.43 [0.15 to 0.79]) was reported for ultra-low compared with low concentration, this was not sustained at 5 min (OR 0.12 [0.00 to 2.10]). Ultra-low concentration local anaesthetic for labour epidural achieves similar or better maternal and neonatal outcomes as low and high concentration, but with reduced local anaesthetic consumption.
Learn More >SignificanceCartilage mineralization is imperative in various processes such as skeletal growth and fracture repair. However, this process may also be pathological, as in the case of the degenerative joint disease, osteoarthritis (OA). Using a posttraumatic OA model (PTOA), we find that cartilage-specific genetic nulls caused severe synovitis and mineralization of the lateral joint compartment, due to augmented gene expression. Conversely, cartilage-specific nulls exhibited impaired synovitis and mineralization of the lateral joint, accompanied by a reduction of local pain. Consistently, transcriptomic profiles of -ablated chondrocytes exhibited enhanced anabolism, yet impaired pathways related to calcification and inflammation. Accordingly, cartilage mineralization of the lateral joint compartment relies on amplified inflammatory pathways, contributing to articular damage following PTOA.
Learn More >Chronic neuropathic pain emerges from either central or peripheral lesions inducing spontaneous or amplified responses to non-noxious stimuli. Despite different pharmacological approaches to treat such a chronic disease, neuropathic pain still represents an unmet clinical need, due to long-term therapeutic regimens and severe side effects that limit application of currently available drugs. A critical phenomenon involved in central sensitization is the exchange of signalling molecules and cytokines, between glia and neurons, driving the chronicization process. Herein, using a chronic constriction injury (CCI) model of neuropathic pain, we evaluated the efficacy of the mu (M-) and delta (D-) opioid receptor (-OR) targeting agent LP2 in modulating connexin-based heterocellular coupling and cytokine levels. We found that long-term efficacy of LP2 is consequent to MOR-DOR targeting resulting in the reduction of CCI-induced astrocyte-to-microglia heterocellular coupling mediated by connexin 43. We also found that single targeting of DOR reduces TNF and IL-6 levels in the chronic phase of the disease, but the peripheral and central discharge as the primary source of excitotoxic stimulation in the spinal cord requires a simultaneous MOR-DOR targeting to reduce CCI-induced neuropathic pain.
Learn More >SignificanceTransmembrane signaling through G protein-coupled receptors (GPCRs), originally described as requiring coupling to intracellular G proteins, also uses G protein-independent pathways through β-arrestin recruitment. Biased ligands, by favoring one of the multiple bioactive conformations of GPCRs, allow selective signaling through either of these pathways. Here, we identified Serodolin as the first β-arrestin-biased agonist of the serotonin 5-HT receptor. This new ligand, while acting as an inverse agonist on G signaling, selectively induces ERK activation in a β-arrestin-dependent way. Importantly, we report that Serodolin decreases pain intensity caused by thermal, mechanical, or inflammatory stimuli. Our findings suggest that targeting the 5-HTR with β-arrestin-biased ligand could be a valid alternative strategy to the use of opioids for the relief of pain.
Learn More >Existing pharmacotherapies acting on the opioid receptor system have been extensively used to treat chronic pain and addictive disorders. Nevertheless, the adverse side effects associated with opioid therapy underscore the need for concerted measures to develop safer analgesics. A promising avenue of research stems from the characterization of a sodium-dependent allosteric regulation site housed within the delta-opioid receptor and several other G protein-coupled receptors (GPCRs), thereby revealing the presence of a cluster of sodium and water molecules lodged in a cavity thought to be present only in the inactive conformation of the receptor. Studies into the structure-function relationship of said pocket demonstrated its critical involvement in the functional control of GPCR signaling. While the sodium pocket has been proposed to be present in the majority of class A GPCRs, the shape of this allosteric cavity appears to have significant structural variation among crystallographically solved GPCRs, making this site optimal for the design of new allosteric modulators that will be selective for opioid receptors. The size of the sodium pocket supports the accommodation of small molecules, and it has been speculated that promiscuous amiloride and 5'-substituted amiloride-related derivatives could target this cavity within many GPCRs, including opioid receptors. Using pharmacological approaches, we have described the selectivities of 5'-substituted amiloride-related derivatives, as well as the hitherto undescribed activity of the NHE1 inhibitor zoniporide toward class A GPCRs. Our investigations into the structural features of the delta-opioid receptor and its ensuing signaling activities suggest a bitopic mode of overlapping interactions involving the orthosteric site and the juxtaposed Na pocket, but only at the active or partially active opioid receptor.
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